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Congenital and Perinatal Infections

Infections in the newborn infant can be classified as congenital or perinatal.


It is important to make this distinction as the clinical presentations, causative
organisms, diagnostic approaches, treatments and long-term considerations
differ for these two groups. A congenital infection is an infection seen in the
newborn infant that was acquired transplacentally during the first, second, or
early third trimester. In contrast, a perinatal infection is acquired either around
the time of delivery or during the first week of extrauterine life.

Congenital infections
The incidence of congenital infection in the fetus and newborn infant is
relatively high at 0.5-2.5%. The most common causative agents are rubella
virus, cytomegalovirus (CMV), Toxoplasma gondii, Treponema pallidum, human
immunodeficiency virus (HIV). Despite the diversity of these organisms, many
produce similar syndromes in the newborn infant grouped under the acronym
TORCH. Common manifestations of congenital infections include growth
retardation, hepatomegaly, splenomegaly, jaundice (secondary to direct
hyperbilirubinemia), hemolytic anemia, petechiae and ecchymoses,
microcephaly, hydrocephaly, and pneumonitis. However, the majority of affected
infants are entirely asymptomatic.
Rubella syndrome. The incidence of congenital rubella syndrome is 0.5
per 1000 live births. Infants are usually born small for gestational age. Common
clinical findings include: purpura, thrombocytopenia, hepatosplenomegaly,
cardiac defects, eye defects (glaucoma and cataracts), pneumonia and
meningoencephalitis. Diffuse purpuric lesions on the skin resembling a
"blueberry muffin", represent cutaneous extramedullary hematopoietic tissue
that may be seen in this and other congenital infections. Congenital rubella
infection can be diagnosed with an elevated anti-rubella IgM titer in the perinatal
period or high anti-rubella IgG titers throughout the first year of life. Virus can
also be isolated from a throat swab, CSF or urine. Common long term problems
seen in infants with congenital rubella include communication disorders, hearing
defects, mental and/or motor retardation, microcephaly, learning deficits, balance
and gait disturbances, and behavioral problems. Although live attenuated rubella
virus vaccine is available to prevent the disease, there is no specific therapy for
congenital rubella.
Congenital cytomegalovirus infection. CMV infection occurs in roughly
1% of all neonates with those who are not congenitally infected contracting the
infection possibly through breast milk. Twelve percent of these infants will die and
more than 90% of survivors will suffer late complications, most commonly
sensorineural hearing loss. Congenital CMV infection may be the result of a
newly acquired maternal infection or a reactivated old maternal infection.
Although less common, newly acquired maternal infection poses a much higher
risk of severe disease and a worse prognosis. Ninety percent of infected
newborns are surprisingly asymptomatic at birth. However, those that are
symptomatic are small for gestational age and often present with petechiae,
ecchymoses, thrombocytopenia, jaundice, direct hyperbilirubinemia, anemia,
hepatosplenomegaly, elevated SGOT, microcephaly, seizures and chorioretinitis.
The diagnosis of congenital CMV infection is best made by isolating the virus in
urine culture. Periventricular calcifications can be seen on cranial ultrasound. Of
the affected infants that survive the neonatal period, 1/3 will have hearing loss,
one third will have neuromuscular disorders (seizures or spasticity) and a few will
have vision problems secondary to chorioretinitis. Although there is no specific
therapy for congenital CMV infection, trials examining the effectiveness of
ganciclovir, alpha interferon and CMV immune globulin are underway.
Congenital toxoplasmosis. The incidence of congenital toxoplasmosis
infection varies with geographic location and local dietary habits. Maternal
toxoplasma infection is usually due to ingestion of tissue cysts found in raw or
undercooked meats or consumption of water or other foods containing oocysts
from infected cats. Congenital infection with Toxoplasmosis gondii occurs during
maternal parasitemia. In the neonate, the primary focus of toxoplasma infection
is in the central nervous system, leaving necrotic, calcified cystic lesions
dispersed within the brain. Less commonly, similar lesions can be found in liver,
lungs, myocardium, skeletal muscle, spleen and other tissue. Approximately 85%
of infants with congenital infection have normal examinations and are
asymptomatic. Those infants that exhibit illness at birth frequently present with
fever, hepatosplenomegaly, jaundice, rash and pneumonitis. The classic triad of
toxoplasmosis, chorioretinitis, hydrocephalus and intracranial calcification occurs
in only a small proportion of symptomatic patients. Abnormal laboratory findings
include anemia, thrombocytopenia, eosinophilia, and abnormal CSF studies.
Seizures, mental retardation, spasticity, and relapsing chorioretinitis are common
long-term complications of congenital toxoplasmosis, even if not present at birth.
Antenatal ultrasound can suggest the diagnosis of congenital toxoplasma
infection when bilateral, symmetric ventricular dilatation, intracranial
calcifications, increased placental thickness, hepatomegaly and ascites are
noted. Postnatal diagnosis is also made by detection of anti-Toxoplasma IgM
antibodies in the infant's serum. Treatment, antenatally and postnatally, consists
of pyrimethamine and sulfadiazine. Spiramycin may also be used, if available.
Historically, prognosis in untreated infants is poor. However, with recent
advances in antenatal diagnostic capabilities and available medical therapies, the
frequency of major neurologic sequelae has decreased.
Syphilis is caused by the spirochete Treponema pallidum. Transplacental
transmission usually occurs during the second half of pregnancy. Most infants
born to mothers with primary or secondary syphilis have congenital infection;
though only half of those who are infected are symptomatic. Because congenital
syphilis is associated with significant neurodevelopmental morbidity, it is
imperative that both maternal status and infant risk for syphilis be checked in all
pregnancies. Early features of congenital syphilis include hepatosplenomegaly,
skin rash, anemia, jaundice, metaphyseal dystrophy, periostitis and CSF
abnormalities including elevated protein and mononuclear pleocytosis. However,
in some cases, the infant is asymptomatic and may not develop any signs or
symptoms of congenital infection for weeks or months. "Snuffles" is obstruction
of the nose with initial clear discharge progressing to purulent or sanguineous
discharge. It is seen in infants with congenital syphilis usually after the newborn
period. Detection of IgM-FTA-ABS (fluorescent treponemal antibody absorption) in
the newborn's blood is the most reliable method of diagnosing congenital
syphilis. However, this test is not always positive early on in life, thus repeat
testing at 3 to 4 week intervals is frequently indicated. Treatment for both the
pregnant mother and baby is penicillin G. Despite antibiotic therapy, it is
recommended that infants undergo repeat blood and CSF testing during the first
12-15 months of life until negative or stable low titer levels are achieved. Vision,
hearing and developmental evaluations are also indicated before three years of
age in infants with congenital syphilis.

Perinatal infections
Perinatally acquired infections are those that are acquired either around the
time of delivery or during the first week of extrauterine life. Common pathogens
include bacteria, such as group B streptococci, E. Coli, and Listeria, herpes
simplex virus, hepatitis viruses and human immunodeficiency virus. Infants with
perinatally acquired viral infections are often normal at birth, developing illness
later in life.
A few pathogens like cytomegalovirus (CMV) can cause both congenital
and perinatally acquired infection in the newborn with striking contrasts in
presentation. The infants with congenital infections can present with growth
restriction, anemia, thrombocytopenia, extramedullary hematopoiesis, and
intracranial calcifications, all indicative of a chronic process; namely, congenital
CMV infection that was transmitted transplacentally during the first or second
trimester of pregnancy. Perinatally, CMV can be transmitted through breast milk
or vaginal secretions. Premature infants however, are particularly susceptible to
transmission through transfusion of blood products. The resulting syndrome is
characterized by shock, pneumonitis and lymphocytosis. The role of ganciclovir in
perinatally acquired CMV infection is unclear.
The majority of neonatal herpes simplex virus (HSV) infection is
acquired from the maternal genital tract with an incidence of approximately 1
case per 3500 live births. However, infection may also be acquired after birth
from mother or other persons with non-genital tract lesions (e.g., oral herpes,
herpetic whitlow) following close contact with the infant or handling. Primary
maternal infection is associated with a 50% risk of perinatal/neonatal infection,
while a risk of <5% is seen with recurrent maternal infection. Of note, active HSV
lesions are present at the time of delivery in only 1/3 of mothers of affected
infants. Several defects in cellular immune function contribute to neonatal
susceptibility to HSV. Perinatally acquired HSV infection results in massive
coagulation necrosis of the liver, lungs, adrenal glands and brain. Most infants are
asymptomatic at birth, developing illness during first 1 to 2 weeks of life. Clinical
illness can be characterized as being localized or disseminated. Disseminated
illness can be further described as those with and those without central nervous
system involvement. Systemic symptoms of disseminated HSV infection usually
present towards the end of the first week of life, including poor feeding, lethargy,
fever, irritability, and seizures with rapid progression to hypotension,
disseminated intravascular coagulation, apnea and shock. Skin vesicles are
present in less than half of patients. With antiviral therapy, 15-20% of patients
die and 40-55% of survivors suffer long-term neurologic impairment. Localized
disease may involve the central nervous system alone, the central nervous
system and skin, eyes, and oral mucosa or only the skin, eyes and oral mucosa.
Except in cases of isolated viral encephalitis, HSV is readily recovered in culture
from scrapings of skin vesicles, blood, cerebrospinal fluid, conjunctivae,
respiratory secretions, and urine. Once neonatal HSV infection is suspected,
antiviral therapy should be started immediately. Parenteral acyclovir is the
treatment of choice for herpes neonatorum. Treatment duration varies
depending on whether the infection involves the CNS and/or is disseminated.
Despite antiviral therapy, overall outcome for survivors is poor. More than half of
infants who survive disseminated disease will develop microcephaly, spasticity,
paralysis, seizures, deafness, or blindness. Those with skin involvement may be
subject to recurrent vesicular outbreaks for several years. Of note, HSV can also
be transmitted in utero during the first or second trimesters of pregnancy
(congenital infection). Those fetuses that are not stillborn or spontaneously
aborted demonstrate a syndrome similar to other congenital viral infections like
CMV. Treatment is supportive as acyclovir has no proven benefit for these
infants.
Hepatitis. The most important of the hepatitis viruses for the general
pediatrician is Hepatitis B. The virus is found primarily in the liver parenchyma,
but can be found in circulating blood from a few days to many years. Regardless
of maternal acute or chronic infection, the virus rarely crosses the placenta, thus
perinatal/neonatal infection is most likely acquired from infected maternal blood
encountered during the delivery process. Overall, there is 60-70% chance of
transmission during delivery if mother has an acute infection at that time.
Mothers may also be carriers which still has a risk of transmission to the
newborn. By 2 to 6 months of age, liver enzymes are often elevated and infants
are antigen seropositive. Occasionally, infection may present with jaundice,
fever, hepatomegaly and anorexia, followed by complete recovery or chronic
active disease. Approximately 95% of perinatally acquired HBV infection can be
prevented by early active and passive immunoprophylaxis of infants born to
HBsAg positive mothers. Infants born to HBsAg positive mothers should receive
the initial dose of hepatitis B vaccine and hepatitis B immune globulin (HBIG)
within 12 hours of birth (given at separate injection sites). Infants born to
unscreened mothers should receive their first hepatitis B vaccine within 12 hours
of birth while awaiting maternal blood test results. If the mother should be found
to be HBsAg positive, HBIG should be given within the first week of life. All
infants should complete the hepatitis B immunization series by 6 months of age.
Infants born to HBsAg positive mothers should be tested for anti-HBsAg
antibodies and HBsAg 1 to 3 months after the third dose of vaccine is given to
determine those who may be chronically infected and those who may require
additional doses of the vaccine. Breastfeeding by an HBsAg positive mother has
not been shown to cause hepatitis B infection in infants.
Once seen exclusively in children who had received blood products,
pediatric human immunodeficiency virus (HIV) infection is now
overwhelmingly the result of perinatal transmission. There are three distinct
modes of transmission of human immunodeficiency virus (HIV) from mother to
fetus. Congenital HIV infection results from the transplacental transmission of
virus during early pregnancy. Intrapartum transmission may occur following
exposure of the infant to mother's blood or as a result of maternal-fetal
transfusion during the delivery. Perinatal infection with HIV can occur either
during the birthing process or shortly after birth through breastfeeding. Risk
factors associated with perinatal HIV transmission include maternal viral load
(plasma and genital tract), primary infection of late stage HIV, low CD4 count,
STDs/other co-infections, pre-term delivery, increasing duration of rupture of
membranes, placental disruption, invasive fetal monitoring (eg. scalp probes),
vaginal delivery and lack of AZT prophylaxis. The transmission rate from mother
to infant is approximately 20-30%. However, recent studies have shown that for
select HIV-infected women, zidovudine (AZT) may decrease transmission to 8% of
their infants. Maternal treatment with AZT in combination with elective cesarean
section delivery prior to rupture of membranes and the onset of labor has shown
further reduction of the transmission rate to 2%. Infants with congenital infection
present in a similar fashion to other congenital infections and may also exhibit
craniofacial abnormalities. Infants with perinatally acquired infection are usually
asymptomatic at birth. To maximize the opportunity to prevent perinatal
transmission of HIV infection, maternal HIV status should be determined during
the first trimester of pregnancy. Anti-retroviral therapy should be started in those
found to be HIV positive. During labor and delivery, AZT, 2mg/kg should be
administered IV during the first hour, then 1mg/kg per hour until delivery. The
infant should then be started on AZT syrup, 8-12 hours after birth, 2mg/kg QID
until 6 weeks of age when the infant's HIV status can be determined. Detection
of HIV antibody by ELISA or Western blot in the newborn is complicated by
transplacental passage of maternal IgG and should not be performed before 18
months of age. Detection of HIV DNA by PCR is the preferred test for diagnosis of
HIV infection in infants. Testing should be performed at birth, then at 1-2 months
of age, and a third time between 3 and 6 months of age. Any time an infant tests
positive, a second repeat specimen should be obtained immediately to confirm
the diagnosis of HIV infection. Viral culture for HIV can also be done; however,
issues of cost, regional availability and delay in reporting results make it less
useful than HIV DNA by PCR. Umbilical cord blood should not be used for testing.
An infant with at least 2 negative HIV virology tests from separate specimens, 1
of which was performed at 1 month of age and 1 of which was performed after 4
months of age can be considered "not infected with HIV". Finally, because
transmission of HIV through breastmilk has been reported, counseling to
discourage breastfeeding should be provided to all mothers who are HIV positive.

Questions
1. What physical findings suggest that an infant has a congenital infection
(TORCH)?
2. How does a congenital infection differ from an infection that is acquired
perinatally?
3. What are the most common causes for congenital infection?
4. True/False: A term infant with a normal physical exam and no risk
factors for infection may have congenital infection.
5. Periventricular calcifications in the brain are seen with which congenital
infection? Diffuse calcifications?
6. True/False: An infant born to a woman with recurrent herpes infection is
at higher risk for developing herpes neonatorum than one born to a woman with
primary herpes infection at the time of delivery?
7. Administration of what agents can prevent 95% of perinatally acquired
hepatitis B infections?
8. True/False: Breastfeeding should be encouraged in all mothers who are
HIV positive, but do not have AIDS.
Answers to questions
1. Small for gestational age, microcephaly, jaundice, pale skin, petechiae,
blueberry muffin spots, hepatomegaly, and splenomegaly
2. A congenital infection is an infection seen in the newborn infant that
was acquired transplacentally during the first, second, or early third trimester. A
perinatal infection is acquired either around the time of delivery or during the 1st
week of extrauterine life.
3. Rubella virus, cytomegalovirus (CMV) Toxoplasma gondii, Treponema
pallidum, human immunodeficiency virus (HIV)
4. True
5. Periventricular calcifications are seen in congenital CMV while diffuse
calcifications in the brain are seen in congenital toxoplasmosis.
6. False
7. Hepatitis B vaccine and hepatitis B immune globulin.
8. False